Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene
Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene
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DOI：
10.1016/j.ymthe.2004.06.115
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发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Bertino, JR
中科院分区：
文献类型：
--
作者：
Budak-Alpdogan, T;Alpdogan, O;Bertino, JR
含有双突变二氢叶酸还原酶-胞苷脱氨酶融合cDNA（F/S DHFR-CD）与IRES-eGFP的基于SFG的逆转录病毒双顺反子载体赋予对甲氨蝶呤（MTX）和阿糖胞苷（ara-C）两者的抗性。在用融合基因或对照基因（eGFP-IRES-NeoR）转导的骨髓移植后两周，将人淋巴瘤（SKI-DLCL-1）细胞皮下注射到非肥胖糖尿病/严重联合免疫缺陷小鼠的侧腹中。在模拟移植小鼠中，移植后MTX/ara-C的最大耐受剂量（MTD）（15/10 mg/kg/天，x3）无法控制肿瘤生长。融合基因的转移允许MTX/ara-C（25/15 mg/kg/天，x4）的剂量比MTD高两倍。肿瘤负荷定义了移植后化疗的有效性;肿瘤接种后48小时的早期治疗提供了无肿瘤生存期，而在肿瘤明显生长（7天）后开始治疗延迟了肿瘤生长的中位时间为28天。此外，早期治疗组外周血和骨髓细胞中的基因表达高于晚期治疗组（P < 0.05），表明早期治疗允许富集转导的骨髓祖细胞。这些结果鼓励使用这种逆转录病毒融合基因构建体的临床研究。
An SFG-based retroviral bicistronic vector containing a double-mutant dihydrofolate reductase-cytidine deaminase fusion cDNA (F/S DHFR-CD) with IRES-eGFP confers resistance to both methotrexate (MTX) and cytarabine (ara-C). Two weeks after transplantation with marrow transduced with either a fusion or a control gene (eGFP-IRES-NeoR), human lymphoma (SKI-DLCL-1) cells were injected sc into the flanks of nonobese diabetic/severe combined immune deficiency mice. In mock-transplanted mice, maximal tolerated dose (MTD) of posttransplant MTX/ara-C (15/10 mg/kg/day, x3) was unable to control tumor growth. Transfer of the fusion gene allowed doses of MTX/ara-C (25/15 mg/kg/day, x4) twofold higher than the MTD to be tolerated. The tumor burden defined the efficiency of posttransplant chemotherapy; early treatment, 48 h after tumor inoculation, provided tumor-free survival, while starting treatment after having palpable tumor growth (7 days) delayed tumor growth a median time of 28 days. In addition, the early treated group had higher gene expression in peripheral blood and marrow cells than the late treated group (P < 0.05), suggesting that early treatment allowed for enrichment of transduced marrow progenitors. These results encourage clinical studies using this retroviral fusion gene construct.